Gait slowing and balance problems often develop in older adults in the absence of a specific disease or acute clinical event, but rather as a consequence of age-related changes in the nervous, musculoskeletal or cardiorespiratory system. A multidisciplinary study of such unexplained age-related mobility impairment looks both at its peripheral and central contributors and it therefore requires a strong foundation in geriatric assessment, neuroimaging and neuroepidemiology. Dr. Rosano is a physician neuroepidemiologist who aims to prevent age-related mobility impairment by targeting structural and functional brain integrity. As a new Pepper scholar and junior faculty, her line of research provides evidence for an independent association between subclinical white matter (WM) abnormalities and focal gray matter (GM) atrophy with mobility. She now seeks external funding for a 3 year career award application to address the following three aims: 1) to identify the earliest structural WM and GM changes associated with unexplained age-related mobility impairment, 2) to examine the spatial and temporal relationship of WM and GM subclinical abnormalities in mobility-related areas and 3) to identify the possible causes and risk factors of such brain abnormalities. The application consists of two complementary projects. In Project 1, she will utilize existing paired brain MRIs collected 5 year apart in 2,109 participants of the Cardiovascular Health Study (CHS) to measure the association between changes in focal WM hyperintensities and GM atrophy with mobility. In Project 2, she will use advanced neuroimaging techniques to acquire 250 brain MRIs from the Health, Aging and Body Composition study participants (Health ABC) and she will measure WM, GM and cortical connections' abnormalities that are undetectable with conventional MRI. Dr. Rosano will exploit the CHS and Health ABC unique longitudinal cohorts data on mobility, health related factors, cardiovascular and inflammatory markers that span a follow-up time of over 10 years. Dr. Anne Newman, an internationally recognized leader in multidisciplinary aging research, and a team of experts in cerebrovascular epidemiology, mobility research, and geriatric neuroimaging will assist Dr. Rosano's work. This award will consolidate Dr. Rosano's knowledge of longitudinal data analysis, will advance her expertise of cutting-edge neuroimaging techniques, and will strengthen her ability to independently execute large longitudinal epidemiological studies. [unreadable] [unreadable] [unreadable]